Neoplasie Endocrine Multiple(MEN)

Emanuele BosiUniversità Vita-Salute San Raffaele

A.A. 2009/10

Multiple Endocrine Neoplasia (MEN)

Le Neoplasie Endocrine Multiple (Multiple Endocrine Neoplasia, MEN) sono patologie familiari connotate dalla presenza nello stesso paziente di lesioni iperplastiche, adenomatose o adenocarcinomatose in due o più ghiandole endocrine.

MEN: general features

The MEN syndromes differ from other hereditary cancer syndromes in that most tumor growth occurs in hormone-secreting glands.

This feature has two primary consequences of clinical importance:

1. the excess hormone production often results in well-defined hormonal syndromes with characteristic symptoms and medical sequelae.

2. the excess hormone production serves as a sensitive tumor marker that is useful for making a diagnosis, determining response to therapy, and screening asymptomatic patients.

Classificazione

In base alle ghiandole endocrine interessate si distinguono le

seguenti forme:

MEN 1

MEN2

Altre (Sindromi miste)

Classificazione: MEN1

MEN 1 - Wermer’s syndrome

• Paratiroidi: Iperplasia o adenoma (paratormone)

• Pancreas endocrino e duodeno: Iperplasia, adenoma o carcinoma (gastrina, insulina, glucagone, somatostatina, PP, VIP)

• Ipofisi: Iperplasia o adenomi (prolattina, GH, ACTH)

• Altre manifestazioni cliniche meno comuni: carcinoide, feocromocitoma, lipomi sottocutanei o viscerali

Classificazione: MEN2

MEN 2A

• MTC: Carcinoma Midollare della Tiroide

• Feocromocitoma

• Iperplasia o adenoma delle paratiroidi

In associazione a:

- amiloidosi e lichen cutaneo

- malattia di Hirschsprung

- FMTC: Carcinoma Midollare Familiare della Tiroide

MEN 2B

• MTC: Carcinoma Midollare della Tiroide

• Feocromocitoma

• Neurinomi delle mucose e gastrointestinali

• Habitus marfanoide

Classificazione: altre, forme miste

Carcinoma midollare familiare della tiroide: almeno 4 membri affetti senza altre endocrinopatie

Von Hippel Lindau: feocromocitoma, emangioblastoma retinico o SNC, carcinoma cellule chiare del rene, tumori isole pancreatiche, ..

Neurofibromatosi associate a MEN: feocromocitoma, macchie caffè-latte, neurofibromi, ..

Sindrome di Cowden: carcinoma non midollare della tiroide (papillare o follicolare), neoplasie di cute, mammella, mucosa orale, utero

Carney complex: tumori endocrini (tiroide, ipofisi, corticosurrene), pigmentazione cutanea, mixomi, schwannomi

Classificazione WHO

Solcia E, Kloppel G, Sobin LH (2000)

Histological Typing of Endocrine Tumours. World Health Organization International

Histological Classification of Tumours.

Solcia E, Kloppel G, Sobin LH (2000)

Histological Typing of Endocrine Tumours. World Health Organization International

Histological Classification of Tumours.

A revised clinicopathological classification of neuroendocrine

tumors of the gastroenteropancreatic tract has been

developed under the auspices of the World Health

Organization (WHO) according to advances in the field of

tumor biology.

Classificazione WHO: Novità principali

Nomenclatura

Abbandono del termine “carcinoide” a favore di tumore o carcinoma: “instead of carcinoid, the WHO classification published in 2000 uses the general terms neuroendocrine tumor and neuroendocrine carcinoma”

Utilizzo combinato di dati anatomo-clinici e funzionali

Volume, presenza di metastasi, presenza di angioinvasione, tipo di secrezione ormonale, presenza o meno di sindrome clinica associata: “On the basis of localization and of various morphological and biological criteria, we distinguish between benign neuroendocrine tumors, tumors with uncertain malignant potential, and tumors showing low-grade

and high-grade malignancy”.

Suddivisione per sede

Stomaco, pancreas, duodeno, digiuno-ileo, appendice, colon-retto.

Nomenclatura

Abbandono del termine “carcinoide” a favore di tumore o carcinoma: “instead of carcinoid, the WHO classification published in 2000 uses the general terms neuroendocrine tumor and neuroendocrine carcinoma”

Utilizzo combinato di dati anatomo-clinici e funzionali

Volume, presenza di metastasi, presenza di angioinvasione, tipo di secrezione ormonale, presenza o meno di sindrome clinica associata: “On the basis of localization and of various morphological and biological criteria, we distinguish between benign neuroendocrine tumors, tumors with uncertain malignant potential, and tumors showing low-grade

and high-grade malignancy”.

Suddivisione per sede

Stomaco, pancreas, duodeno, digiuno-ileo, appendice, colon-retto.

Classificazione WHO: Criteri

Parametri patologici

Clinica

Contesto clinico generale

Secrezione ormonale

Parametri patologici

Clinica

Contesto clinico generale

Secrezione ormonale

Classificazione WHO: Criteri

Parametri patologici (sede, dimensione, coinvolgimento delle tonache di parete/diffusione extraorgano, indice proliferativo, angio-invasione, linfonodi, metastasi, residuo di malattia):

Tumori endocrini ben differenziati (benigni/comportamento biologico incerto) funzionanti e non funzionanti

Carcinomi endocrini ben differenziati (basso grado di malignità) funzionanti e non funzionanti

Carcinomi endocrini scarsamente differenziati (alto grado di malignità)Carcinomi misti endocrini/esocriniClinica:Funzionanti/non funzionantiContesto clinico generale:(stomaco: tumori endocrini associati o meno ad ipergastrinemia)Produzione ormonale:Dimostrabile con metodiche immunoistochimiche

Tumori differenziatiTumori differenziati

Benigni

A comportamento biologico incerto

CarcinomiCarcinomi Ben differenziati (basso grado di malignità)

Scarsamente differenziati (alto grado di malignità)

Tumori mistiTumori misti

Esocrini-endocrini

Tumori Endocrini ben differenziati a comportamento benigno vs incerto

dimensione (1 cm [2 cm per pancreas e appendice]) e angioinvasione

Tumori Endocrini ben differenziati a comportamento benigno vs incerto

dimensione (1 cm [2 cm per pancreas e appendice]) e angioinvasione

Tumori Endocrini vs carcinomi

infiltrazione della tonaca muscolare (mesenteriolo per appendice) e presenza di metastasi

Tumori Endocrini vs carcinomi

infiltrazione della tonaca muscolare (mesenteriolo per appendice) e presenza di metastasi

Classificazione WHO

MULTIPLE ENDOCRINE NEOPLASIA

MEN TYPE 1

Wermer’s syndrome

GeneticAutosomal-dominant condition that occurs as a result of

inactivating mutations of MEN1 gene

The MEN 1 gene is located at chromosome 11q13 and consist

of 10 exons with a 1830-bp coding region that encodes a

novel 610-amino acid protein, referred to as MENIN.

The presumed unifying mechanism for tumor formation in Men

1 involves loss of MENIN function in a tumor precursor cell.

MEN TYPE 1 Wermer’s syndrome

Diagnosi Genetica

sostituzione C-G in posizione 1561 dell’esone 10 [sostituzione AA Arg-Gly in posizione 521]

sostituzione T-C in posizione 7257 dell’esone 9 [sostituzione AA Phe-Ser in posizione 416]

sostituzione C-G in posizione 1561 dell’esone 10 [sostituzione AA Arg-Gly in posizione 521]

sostituzione T-C in posizione 7257 dell’esone 9 [sostituzione AA Phe-Ser in posizione 416]

MEN1: General features

• Multifocal nature of the disease process within a single

organ.

• Hyperplasia adenoma carcinoma

• a neoplastic process in one organ may affect the

progression in another organ (i.e. pancreatic tumor may

stimulate growth of a pituitary tumor).

• the syndrome evolves in 30-40 years and the manifestation

will in large parte on when the syndrome is identified.

•The prevalence of MEN1 has been estimated at 1 in 20-40,000

individuals

Hyperparathyroidism Hyperparathyroidism Entero-Pancreatic TumorEntero-Pancreatic Tumor Pituitary Pituitary Adenoma Adenoma

MEN 1 MEN 1

90-100% 90-100% 80% 80% 50-60% 50-60%

Percent of MEN 1 Clinical Features

MEN1: sindromi cliniche da iperplasia, adenomi, carcinomi endocrini

Paratiroidi: Iperparatiroidismo primitivo

Pancreas endocrino e duodeno:

• Gastrinoma (Zollinger-Ellison)

• Insulinoma

• Glucagonoma

• Somatostatinoma

• VIPoma (Watery Diarrhea Syndrome)

• PPoma, non secernenti

Ipofisi: prolattina, GH, ACTH, non secernenti

Insulinoma: Clinica

Neuroglicopenia Cambiamenti di personalità Confusione Epilessia Coma

Altri sintomi Appetito Fatica Nausea, vomito Neuropatia periferica

Neuroglicopenia Cambiamenti di personalità Confusione Epilessia Coma

Altri sintomi Appetito Fatica Nausea, vomito Neuropatia periferica

Eccesso di catecolamine Diaforesi Pallore Tachicardia

51%

14%

22%

Segni e sintomiSegni e sintomiSegni e sintomiSegni e sintomi Distribuzione del tumoreDistribuzione del tumoreDistribuzione del tumoreDistribuzione del tumore

Diabete Mellito

Sindrome endocrina multipla

Eritema necrolitico migrante

Sindrome neoplastica

Diabete Mellito

Sindrome endocrina multipla

Eritema necrolitico migrante

Sindrome neoplastica

Sindrome neoplasticaSindrome neoplastica

Calo ponderaleCalo ponderale DiarreaDiarrea Trombosi venosa profondaTrombosi venosa profonda AnemiaAnemiaEritema necrolitico migranteEritema necrolitico migrante

Sindrome neoplasticaSindrome neoplastica

Calo ponderaleCalo ponderale DiarreaDiarrea Trombosi venosa profondaTrombosi venosa profonda AnemiaAnemiaEritema necrolitico migranteEritema necrolitico migrante

80% MALIGNI80% MALIGNI80% MALIGNI80% MALIGNI

Glucagonoma: Clinica

Segni e sintomiSegni e sintomiSegni e sintomiSegni e sintomi Distribuzione del tumoreDistribuzione del tumoreDistribuzione del tumoreDistribuzione del tumore

5%

15%

80%

Gastrinoma: Clinica

Ulcere

Sintomi da reflusso

Dolore addominale

Diarrea

Ulcere

Sintomi da reflusso

Dolore addominale

Diarrea

Il gastrinoma origina dalle cellule G, localizzate prevalentemente nel duodeno prossimale (83%) e in minor misura nell’antro gastrico, e da popolazioni cellulari denominate D1 a sede pancreaticaIl gastrinoma origina dalle cellule G, localizzate prevalentemente nel duodeno prossimale (83%) e in minor misura nell’antro gastrico, e da popolazioni cellulari denominate D1 a sede pancreatica

spesso multifocali

dimensioni < 1 cm associati a MEN 1

duodenali

spesso multifocali

dimensioni < 1 cm associati a MEN 1

duodenali

singolo

dimensioni > 1 cm sporadico

pancreatici

singolo

dimensioni > 1 cm sporadico

pancreatici

Gastrinoma: Clinica

Test genetico

• La MEN1 dovrebbe essere sospettata nei pazienti con: iperparatiroidismo ad esordio <30 anni o a base multighiandolare o con elevata incidenza familiare; tumori endocrini del pancreas multifocali; Zollinger-Ellison; due endocrinopatie di pancreas, ipofisi, paratiroidi

• Test genetico disponibile; utile in fase precoce per il monitoraggio delle successive endocrinopatie

Therapeutic considerations

Despite its earlier recognition, MEN 1 is the most challenging of

the MEN syndromes.

Each affected patient can be expected to undergo at least two or

more surgical procedures; it is necessary to recognize the high

probability of recurrent or new neoplasms in potentially affected

organ systems and to balance this likelihood against the possible

side effects of intervention, such as

- Hypoparathyroidism

- Hypopituitarism

- Endocrine and exocrine pancreatic insufficency

MULTIPLE ENDOCRINE NEOPLASIA

MEN TYPE 2

Overview

The hallmark of MEN2 is a very high lifetime risk of developing medullary thyroid carcinoma (MTC) more than 95% in untreated patients.

Three clinical subtypes MEN2A, MEN2B, and familial MTC (FMTC) have been defined based on the risk of:- pheochromocytoma- hyperparathyroidism- the presence or absence of characteristic physical features

The prevalence of MEN2 has been estimated at 1 in 35,000 individuals

Definition

The MEN 2 syndrome has been sub-categorized into two

variants called MEN 2A and MEN 2B (formerly MEN 3)

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2

MEN 2 and its clinical variants or syndromes

MEN 2 and its clinical variants or syndromes

MEN 2: genetica e fisiopatologia

Mutation of the c-ret protooncogene have been identified in

93 to 95% of pts with MEN 2.

Two regions of the Ret tyrosine kinase receptor are

mutated

MEN TYPE 2: diagram of the c-ret protoncogene

Percent of MEN 2 Clinical Features by Subtype

SubSubtype type

Medullary Thyroid Medullary Thyroid Carcinoma Carcinoma

PheochromoPheochromocytoma cytoma

Parathyroid Parathyroid Disease Disease

MEN 2A MEN 2A 95% 95% 50% 50% 20-30% 20-30%

FMTC 100% 0% 0%

MEN 2B MEN 2B 100% 100% 50% 50% Uncommon Uncommon

Testing Used in MEN 2

Mutation Mutation Detection Rate Detection Rate

Test Test Type Type

Test Test Availability Availability

MEN 2A MEN 2A 95% 95% DNA-based DNA-based

Clinical Testing

FMTC 85% DNA-based

MEN 2B MEN 2B 95% 95% DNA-based DNA-based

Screening and Risk assessment

• MEN2 accounts for approximately 25% of all cases of MTC and approximately 7% of individuals presenting with apparently sporadic MTC.

• RET genetic testing is considered the standard of care for newly identified MTC patients, regardless of age at diagnosis or family history.

• The identification of a mutation provides essential risk information for the patient’s family members, and genotype-phenotype correlations can help estimate the patient’s risk of developing additional endocrinopathies (eg, pheochromocytoma, primary hyperparathyroidism), provide prognostic information, and guide the surgical management of MTC.

The MEN 2A syndrome consist of

multifocal medullary thyroid carcinoma

unilateral or bilateral pheochromocytoma

parathyroid hyperplasia or adenoma

Approximately 4% to 5% of cases of apparently sporadic

pheochromocytoma occurring before age 50 years are due to

mutations of RET and are thus associated with MEN2A.

MEN2A-associated pheochromocytomas almost always secrete

epinephrine and may or may not secrete norepinephrines. In

addition, malignancy and extra-adrenal location are extremely rare

in MEN2A.

MEN 2A: Overview

MEN 2A: Clinical features

Patients with this syndrome can present with manifestations

of a pheochromocytoma, a thyroid nodule, hypercalcemia

or some combination of the three,

but at present

the routine screening of affected families makes early

thyroid C-cell hyperplasia (elevation of circulating

calcitonin), the most common initial presentation (followed

by Pheochromocytoma in about half pts and parathyroid

abnormalities in 10 to 35%).

Medullary thyroid carcinoma (MTC)Multicentric neoplasm of parafollicular or C cell of thyroid gland.

The first demonstrable abnormality is hyperplasia of C cells

followed by

Histological progression:

nodular hyperplasia

microscopic medullary thyroid carcinoma

frank medullary thyroid carcinoma

The time required for this progression through these histologic stages, is not known but the process may

require decades.

MEN 2A: Clinical features

Pheochromocytoma

Adrenal chromaffin tissue undergoes the same

type of histological progression as that observed

for C cell

Histological progression:

- hyperplasia of chromaffin cells

- nodular hyperplasia

- pheochromocytoma

MEN 2A: Clinical features

Pheochromocytoma

Diagnosis confirmed by:

Biochemical features

CT

MRI

Scanning with MIBG

MEN 2A: Clinical features

IntroductionThe MEN 2B (or MEN 3) syndrome consist of

multifocal medullary thyroid carcinoma

unilateral or bilateral pheochromocytoma

multiple mucosal neuromas

marfanoid habitus

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 B

The hallmark of this syndrome is the presence of characteristic

mucosal neuromas on the distal portion of the tongue, the lips and

subconjunctival areas and throught the gastrintestinal tract.

Multiple Mucosal Neuromas

Multiple Mucosal Neuromas

Multiple Mucosal Neuromas

The clinical course of patients with medullary thyroid carcinoma in MEN 2B is more aggressive than that in MEN 2A.Metastatic disease can occur in children younger than 1 year age and there is shorter average survival time in patients with metastatic disease.

The identification of mucosal neuroma phenotype in a

child should alert the physician to the diagnosis of

medullary thyroid carcinoma

MULTIPLE ENDOCRINE NEOPLASIA TYPE 2 B